Both obesity and unplanned pregnancies are at epidemic levels in the United States. An association between obesity and unplanned pregnancy would, therefore, constitute a significant public health concern. Recent epidemiological studies suggest that obesity may reduce oral contraceptive (OC) efficacy, and that this may be of particular concern with very low-dose OCs (i.e., ethinyl estradiol [EE] = 20 mcg]). Studies have not established what mechanisms might lead to this reduced efficacy. Our long-term goal is to identify the mechanisms leading to failure of OCs in obese women in order to improve contraceptive efficacy for these women. Our main hypothesis is that increased Body Mass Index (BMI) alters OC availability resulting in inadequate hypothalamic-pituitary-ovarian (HPO) axis suppression during OC use in obese women. In this R03 application, we propose to examine synthetic steroid metabolism and gonadotropin pulsatility in 20 ovulatory reproductive-age women [10 normal and 10 obese BMI] placed on a very low-dose OC [20 mcg EE/100 mcg levonorgestrel (LNG)], to focus on whether trends exist that are consistent with our main hypothesis. Our specific aims are: 1. to determine whether obesity affects the pharmacokinetics of OCs. The goal of this aim will be to measure peak and steady state concentrations of circulating OC dosed in a standard cyclic fashion in obese and normal BMI cohorts; (1a) focusing on the differences in EE and LNG steady state levels after one treatment cycle; (1b) the clearance rates with stopping treatment (at the start of the hormone free interval); and (1c) the time to steady state with restarting treatment (at the end of the hormone free interval); 2. To determine whether obesity impairs HPO axis suppression achieved with OC use. The goal of this aim will be to measure gonadotropin pulsatility (pulse amplitude and frequency) and ovarian response (average serum levels for estradiol [E2] and progesterone [P]) in obese and normal BMI cohorts; and 3. To compare FSH, LH, E2, and P levels obtained by blood spots (self-performed finger sticks) versus venipuncture to determine whether blood spot assays represent a reliable alternative to serum assays in reproductive research, as they would minimize the invasiveness and blood volume required in a larger study. [unreadable] [unreadable] [unreadable]